Biological activity is typically conferred by a set of structural features in a molecule that is recognized at a biological target, e.g., a receptor site. These features include steric and electronic features. Such a set of structural, steric and/or electronic features is termed a “pharmacophore.” Natural products and peptides are among compounds that have consistently been found to possess potent and selective biological activity.
Many enzymes and receptors interact with proteins, particularly with a pharmacophoric portion of a protein. Because only a small portion of the protein may be responsible for the pharmacophoric effect, exposing an enzyme or receptor to a peptide containing the pharmacophoric features may have the same effect. Thus, development of synthetic and/or modified peptides or peptide analogs can be used to potentially produce more potent agonists or inhibitors of these enzymes and receptors.
Because many enzymes and receptors interact with protein and/or peptide ligands, synthetic peptides and peptide analogs are promising candidates for biological activity screening assays. Of particular interest are synthetic peptides and/or peptide analogs that may have activity against targets (e.g., receptors and/or enzymes) involved in immunologic reactions. Molecules with strong activity as either agonists or inhibitors may be used to develop new drugs and/or treatments.
In some instances, a particular amino acid or side chain, or a combination of amino acids and/or side chains, possesses pharmacophoric activity. Incorporation of these particular amino acids and/or side chains into a synthetic molecule may produce a compound with a desired biological activity. To facilitate access of these amino acids and/or side chain moieties to the active site on an enzyme or receptor, some researchers have attached the moieties to a scaffold or rigid structure such as, for example, an aromatic ring or a sugar.
In another approach, a peptide can be cyclized to facilitate its interaction with a receptor or an enzyme, thereby improving its pharmacological and/or physiological activity. A cyclic peptide can have several advantages compared to its linear analog including, but not limited to, constrained conformational mobility, defined topology, protection from proteolytic enzymes, and/or altered polarity. Additionally, compared to its linear analog, the cyclic peptide may have increased activity, selectivity, stability, bioavailability, and/or membrane permeability.
Drugs based on macrocyclic compounds (e.g., compounds with large rings containing seven or more carbon atoms) play an important role in modern medicine. Current macrocyclic drugs are almost exclusively derived from natural sources and are either identical (e.g., rapamycin, an immunosuppressant drug used to prevent rejection in organ transplantation) or closely related to naturally occurring macrocycles (e.g., temsirolimus, a drug for the treatment of renal cell carcinoma). However, synthetic macrocyclic compounds will be a valuable source of additional compounds to screen for biological activity and subsequent use in drug development.